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Principal Investigator: Jayanta Debnath
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2023
Award: $713,896
Funding agency: National Institute on Aging
PROJECT SUMMARY
Glial pathology is increasingly recognized as a key feature in neurodegenerative diseases. However, the exact
mechanisms that promotes glial pathology remain unclear. Several studies implicate the autophagy machinery,
a highly conserved lysosomal degradation pathway, in maintaining protein homeostasis in neurons during brain
aging and neurodegeneration. In addition, autophagy regulates the check-and-balance of microglia-mediated
inflammatory response to misfolded proteins, including β-amyloid peptides, hyperphosphorylated Tau, and TDP-
43, which accumulate during neurodegeneration. Collectively, these results underscore the critical and cell type-
specific role of the autophagy machinery in maintaining neuron-glia homeostasis by regulating the trafficking of
intracellular organelles and cargoes, such as misfolded proteins. In the previous funding period, we uncovered
new autophagy-dependent secretory processes in non-neuronal and glial cells, including most notably, LC3-
dependent extracellular vesicle loading and secretion (LDELS). LDELS targets include RNA binding proteins
and extracellular vesicle (EV) cargoes that have been implicated in the pathogenesis of frontotemporal dementia
(FTD). In addition, our results showed that loss of function in FTD gene Progranulin (Grn) leads to age-dependent
endolysosomal defects and hypersecretory phenotypes in microglia that promotes neuronal loss and abnormal
accumulation of the RNA binding protein TDP-43 in Grn-/- mouse brain. Together, these results underscore the
important roles of autophagy and endolysosomal trafficking in microglial activation in FTD. In follow up studies,
we have further expanded the scope of our work and identified a highly regulated mechanism, Secretory
Autophagy during Lysosome Inhibition (SALI), which is critically dependent on multiple ATGs for autophagosome
formation and on Rab27a for vesicle exocytosis. Using TMT-based quantitative proteomics, we uncovered that
loss of Progranulin leads to a marked increase in unconventional myosin Myo5a, a known Rab27a interacting
partner. Given the well-documented role of Rab27a and Myo5a in the transport of intracellular organelles, these
results broach the hypothesis that blockage of endolysosomal trafficking disrupts microglial homeostasis and
promotes secretory autophagy and neurodegeneration in Grn-/- mice. To test this hypothesis, we will: 1) Delineate
how FTD-associated endolysosomal defects influence secretory autophagy and dissect the effects of SALI on
intracellular homeostasis; 2) Scrutinize how secretory autophagy and endolysosomal defects in microglia impact
lipid metabolism and microglial toxicity; and 3) Determine whether genetic autophagy loss mitigates microglial
toxicity and neurodegeneration in Progranulin-deficient mice. Together, the studies proposed in this renewal
harness the unique expertise in Drs. Huang and Debnath’s laboratories and provide critical insights on how SALI
controls the delicate balance of secretion and intracellular trafficking of disease-relevant proteins in microglia to
promote neurodegeneration in FTD.
Terms: <Actin-Activated ATPase><Affect><Alzheimer beta-Protein><Alzheimer's Amyloid beta-Protein><Alzheimer's amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Autophagocytosis><Autophagosome><Autoregulation><Aβ><Brain><Brain Nervous System><Catabolism><Cell Communication and Signaling><Cell Signaling><Cell secretion><Cellular Secretion><Co-culture><Cocultivation><Coculture><Coculture Techniques><Defect><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Degradation Pathway><Degradative Pathway><Disease><Disorder><Dysfunction><Encephalon><Equilibrium><Exocytosis><Follow-Up Studies><Followup Studies><Frontal Temporal Dementia><Frontotemporal Dementia><Functional disorder><Funding><Genetic><Glia><Glial Cells><Gliosis><Homeostasis><Hortega cell><Inflammation Mediators><Inflammatory Response><Intracellular Communication and Signaling><Intracellular Transport><Kolliker's reticulum><Laboratories><Lipid Trafficking><Lipids><Lysosomes><MYH12><MYO5><MYO5A><MYO5A gene><Mediating><Mice><Mice Mammals><Microglia><Modeling><Murine><Mus><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosin, Heavy Chain 12><Myosins><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Non-neuronal cell><Nonneuronal cell><Organelles><PC cell-derived growth factor><PCDGF><PGRN gene><PGRN protein><Pathogenesis><Pathology><Pathway interactions><Phenotype><Phosphatides><Phospholipids><Physiological Homeostasis><Physiopathology><Process><Progranulin><Proteins><Proteomics><RNA-Binding Proteins><Receptor Protein><Regulation><Role><Signal Transduction><Signal Transduction Systems><Signaling><TAR DNA-binding protein 43><TDP-43><TDP43><Testing><Toxic effect><Toxicities><Up-Regulation><Upregulation><Vesicle><Work><a beta peptide><aberrant folded protein><aberrant folded proteins><abeta><abnormal folded protein><abnormal folded proteins><age dependent><age related><age related neurodegeneration><age-related neurodegenerative disease><age-related neurodegenerative disorder><aged brain><aging brain><amyloid beta><amyloid-b protein><autophagy><balance><balance function><beta amyloid fibril><biological signal transduction><cell type><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><extracellular><extracellular vesicles><fat metabolism><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><gitter cell><glial activation><glial cell activation><granulin precursor><hyper-phosphorylated tau><hyperphosphorylated tau><inflammatory mediator><insight><lipid metabolism><lipid transport><loss of function><mesoglia><microglial cell><microgliocyte><misfolded protein><misfolded proteins><myosin Va><myoxin><nano particle><nano-sized particle><nanoparticle><nanosized particle><nerve cell death><nerve cell loss><nerve cement><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuron toxicity><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuronal toxicity><neurotoxic><neurotoxicity><particle><pathophysiology><pathway><perivascular glial cell><progranulin gene><progranulin protein><protein TDP-43><protein TDP43><protein homeostasis><proteostasis><proteotoxic protein><proteotoxin><receptor><social role><soluble amyloid precursor protein><trafficking><transcriptomics>